ARTICLE
Auteur(s) : Esra
Pancar Yuksel, Fatma Aydin, Nilgun Senturk, Tayyar Canturk,
Ahmet Yasar Turanli
Ondokuz Mayis University, School of Medicine, Department
of Dermatology, TR-55139 Kurupelit, Samsun, Turkey
accepté le 18 Février 2009
Vitiligo is an acquired idiopathic disorder of great cosmetic
importance, characterized by circumscribed depigmented macules.
Although several hypotheses on the pathogenesis exist, the exact
pathogenesis of vitiligo still remains unknown. Functional
melanocytes disappear from involved skin by a mechanism(s) that has
not yet been identified. Oxidative stress and the accumulation of
melanocytotoxic compounds is one of the mechanisms which has been
proposed as an explanation [1, 2]. It has been shown in vivo and in
vitro that vitiligo patients accumulate milimolar (mM) levels of
hydrogen peroxide (H2O2) in their epidermis.
It is also well established that mM levels of
H2O2 lead to the inactivation of catalase and
low catalase levels have indeed been identified in the epidermis of
these patients, despite normal mRNA expression [3]. Superoxide
dismutase (SOD) catalyses the reaction in which superoxide radicals
are converted to H2O2 and O2 and
catalase degrades H2O2 to H2O and
O2 [4]. Excessive free radical generation may be related
to a decrease of SOD and catalase activities and as a result
imbalance between oxidative damage and antioxidant enzyme systems
may play an important role in the depigmentation of generalized
vitiligo.
Although several therapeutic options are available for the
treatment of vitiligo, it is still one of the most difficult
dermatological disoders to treat. Narrow band ultraviolet B (nbUVB)
phototherapy is currently considered an effective treatment for
generalized vitiligo, however long duration, high dosages and even
combinations are necessary to achieve complete resolution [5, 6].
Recently, new treatment modalities in vitiligo have been directed
to oxidant-antioxidant systems. So, we hypothesized that support of
the antioxidant system with formulations including Cucumis melo
superoxide dismutase and catalase (Vitix®) could
increase the success of nbUVB treatment in vitiligo.
The purpose of the present study was to investigate the clinical
efficacy of nbUVB plus Vitix® over nbUVB treatment
alone.
Patients and methods
Patient selection
Thirty patients who were admitted to the Dermatology Department of
Ondokuz Mayis University Faculty of Medicine between November
2005-July 2006 and had been clinically diagnosed as having
vitiligo, were involved in this study. The study protocol was
approved by the Committe on Ethics and all patients gave informed
consent. Exclusion criteria were under the age of 18, less than 20%
body surface area involvement as determined by the rule of nines,
pregnancy or lactation, segmental type of vitiligo, any evidence of
spontaneous repigmentation, photosensitivity, known
hypersensitivity to Vitix®, abnormal reactions to UV
radiation, any topical or systemic therapy for vitiligo within the
previous 2 months, cataracts, cardiovascular disease, malignancy,
history of chemotherapy or radiotherapy. To asses the related
diseases with vitiligo, all patients underwent laboratory
examination for complete blood count, thyroid function tests and
blood glucose levels. The personal and family history, duration of
disease, the localization of the lesions and previous therapies
were recorded.
Treatment protocol
The patients were divided into two groups equal in number. The
patients in the first group were treated only with nbUVB whereas
the patients in the second group treated with nbUVB and
Vitix® gel for 6 months. nbUVB was given in a
phototherapy unit (Derma Ringo nbUVB) containing a bank of 45
fluorescent tubes (TL-100 W/01, Phillips, Eindhoven, the
Netherlands) with peak emission between 311 and 312 nm. The
lesional skin of all patients was considered to be Fitzpatrick’s
skin phototype I and the nbUVB treatment was applied to the whole
body three times a week on non-consecutive days. The treatment was
started with 140 mJ/cm2 and increasing irradiation
dose by 25 mJ/cm2 for each subsequent visit. During
the treatment, the eyes were protected by ultraviolet (UV)-blocking
goggles and the genital area was shielded.
In the second group, in addition to nbUVB, topical
Vitix® gel was applied twice daily to all lesions
everyday. In the days of nbUVB treatment, patients applied
Vitix® gel at least 2 hours before receiving
phototherapy. During the treatment period, all patients were
evaluated for adverse effects such as burning, stinging, pruritus
and erythema.
Measurement method
A piece of paper, which had lesion borders marked with an ordinary
ballpoint pen, was immediately placed over the lesion before the
treatment. For each lesion, the borders of projection areas on the
paper were enhanced by redrawing the contours with a pen.
Transparent sheets with points (+) were randomly superimposed on
the paper of the projection area. To estimate the number of points,
the numbers of intersections hitting the projection area were
counted. If the upper right corner of the cross was seen in the
defined area it was included in the count. The total area of each
lesion was estimated by multiplying the representative area of a
point on grid by total number of points counted for the lesion. The
representative area of the points in grid was
0.1002 cm2.
Evaluation of the treatment
Before starting the treatment, lesions on the extremities which had
sharp edges were selected. If possible, more than one lesion for
one patient was included in the study. The area of each selected
lesion was determined by the point counting method [7] before and
after the treatment by the same investigator. Perifollicular and
perilesional pigmentation was accepted as a clinical response to
treatment. The healed area was found by the difference of the first
and the last measured areas, and repigmentation percentages were
calculated.
Based on the repigmentation percentages, the treatment outcome
was classified as follows:
- – < 25% repigmentation: poor response;
- – 26-50% repigmentation: moderate response;
- – 51-75% repigmentation: good response;
- – 76-100% repigmentation: perfect response.
Statistical analysis
The Shapiro-Wilk test was used to determine the distribution of
data. Since the data were not normally distributed, the two groups
were analysed by the non-parametric Mann Whitney U test for
comparing the repigmentation percentages. The level of significance
was set at p < 0.05. Statistical analyses were done using SPSS
15.0 for Windows.
Results
Thirty vitiligo patients (12 males, 18 females; mean age 34 ± 13)
were included in the study. Characteristics of the patients and
previously used treatments are presented in table 1. Twenty one lesions from each group were
evaluated. The mean areas of the lesions before and after treatment
are presented in table 2 and the
clinical response of the patients after treatment are presented in
table 3.
We compared the healing percentages at the end of the treatment
and there was no statistically significant difference between the
patients in either group (p > 0.05). No adverse effects were
noted, so none of the patients required the suspension or
discontinuation of therapy.
Table 1 Characteristics and previously used
treatments
|
Group properties
|
Group 1
|
Group 2
|
|
Age*
|
28 (18, 67)
|
33 (20, 54)
|
|
Duration of disease (year)*
|
3 (1, 28)
|
10 (2, 20)
|
|
Female/Male
|
7/8 (47%/53%)
|
11/4 (73%/27%)
|
|
Family history
|
5 (33%)
|
5 (33%)
|
|
Associated diseases
|
_
|
2 (13%) (thyroid, thyroid + depression)
|
|
Previously used treatments
|
PUVA
|
_
|
2 (13%)
|
|
nbUVB
|
2 (13%)
|
2 (13%)
|
|
Topical steroid
|
6 (40%)
|
7 (47%)
|
|
nbUVB + topical steroid
|
_
|
1 (7%)
|
Table 2 The mean areas of the lesions before and after
the treatment
|
Group 1
|
Group 2
|
|
Mean areas (cm2) (min, max)
|
Before the treatment
|
7.6 (0.7, 40.6)
|
8.2 (0.7, 29.1)
|
|
After the treatment
|
5.3 (0.6, 27.2)
|
4.3 (0.3, 20.6)
|
Table 3 Clinical response of the patients after the
treatment
|
Clinical evaluation
|
Number of lesions (%)
|
|
Group 1
|
Group 2
|
|
Perfect (76-100%)
|
0 (0%)
|
1 (4.8%)
|
|
Good (51-75%)
|
2 (9.5%)
|
4 (19%)
|
|
Moderate (26-50%)
|
8 (38.1%)
|
10 (47.6%)
|
|
Poor (≤ 25%)
|
11 (52.4%)
|
6 (28.6%)
|
Discussion
Oxidative stress, characterized by an increase in free radical
production and insufficient antioxidant defence, has been proposed
as a possible pathogenetic mechanism in vitiligo [8-10]. Since
H2O2 is degraded by catalase, supporting of
the antioxidant sytem with catalase can decrease the
H2O2 and increase the success of the
treatment in vitiligo. In the literature, there are a few studies
using antioxidants in vitiligo treatment and topical pseudocatalase
and topical Vitix® gel were two agents used for this
purpose. In the present study, we used topical Vitix®
with nbUVB therapy but a statistically significant difference could
not be found whether nbUVB therapy was used alone or combined with
Vitix® gel.
Pseudocatalase is a bis-manganese
IIIEDTA-(HCO3–)2 complex, capable
of degradation of H2O2 to O2 and
H2O after photo-activation with UVB or solar
irradiation. After topical application of pseudocatalase
preparation, a reduction of the H2O2 peak was
detected in vivo [11]. So, topical UVB-activated pseudocatalase can
be successfully used for removing epidermal
H2O2 in vitiligo [12]. Schallreuter
et al. used the combination of Dead Sea
climatotherapy/pseudocatalase cream in vitiligo patients and they
proposed that removal of epidermal H2O2 and
the influence of solar UV-light were necessary in the treatment of
vitiligo [13]. In another study, they reported complete
repigmentation on the face and dorsum of the hands in 90% of their
study group, using topical pseudocatalase and calcium [14]. Besides
these, there is also another study which suggested that topical
pseudocatalase was not effective in vitiligo. In this study, the
efficacy of topical pseudocatalase mousse, applied twice daily to
the hands and face of vitiligo patients in combination with
twice-weekly nbUVB phototherapy, was assessed and this treatment
was not shown to be effective [15]. However, the pseudocatalase
formulation used in this study was different from that in other
studies [16].
Recently, a formulation containing Cucumis melo superoxide
dismutase and catalase (Vitix®) has been used for the
treatment of vitiligo. Superoxide dismutase cleans out the
superoxide radicals by degrading O2- to
H2O2 and catalase is the enzyme that degrades
H2O2. In fact, production of
O2- by several mechanisms seems to be central
for the production of H2O2 in the skin. In
the light of numerous basic research results, it is proposed that
the reactive oxygen species (ROS) reduction can be achieved by
topical superoxide dismutase and catalase formulation. Schallreuter
and Rokos studied the efficacy of this formulation in the removal
of ROS using in vitro and in vivo Fourier transform -Raman
spectroscopy and they reported that Vitix® does not have
the capacity to reduce H2O2. In order to test
the clinical efficacy of Vitix®, they treated six
patients with facial vitiligo over 4 months with the application of
the formulation twice daily together with solar exposure for at
least 30 minutes over 4 months and they did not notice any
significant repigmentation [17]. But low patient numbers and short
treatment duration affected the efficacy of this study. Another
study in which Vitix® was used in the literature came
from Kostovic et al. Their study included 22 patients but only
19 completed the 6 months study period. Patients applied the gel
containing catalase and superoxide dismutase twice a day and
received nbUVB 3 times per week. Three (15.79%) patients showed
more than 75%, six (31.58%) patients showed 26%-50% repigmentation
and one (5.26%) patient showed 1%-25% repigmentation, whereas no
repigmentation was recorded in one (5.26%) of 19 patients [18]. The
ratios in our study were lower than the ratios reported by Kostovic
et al., although the treatment protocol and duration were
similar. This can be the result of different patient populations in
different geographical regions and different evalution methods of
the lesions. They estimated the repigmentation grade by comparing
photographs but we used an objective measurement method. Moreover,
we divided the patients into two groups, treated by 2 different
treatment modalities and compared these two groups, whereas
Kostovic et al. evaluated only nbUVB and topical
Vitix® combination treatment. The low patient number and
short duration of treatment were limitations of both studies.
In our study, by dividing patients into two groups we were sure
of the accurate application of the gel by the patients, since it is
difficult to convince patients to apply the gel to only one side
for 6 months. Otherwise inappropriate application of the gel might
be a cause of error in study results. But this time another
question was arising, could this be a possible cause of another
type of error, since the melanocyte loss might not be equivalent on
two patients with vitiligo? Another limitation of our study is the
difference between the groups regarding the duration of disease and
sex ratio. These differences occurred as we randomly recruited the
patients for the treatment protocol. In the literature it is
reported that the best results could be obtained in patients with
recent vitiligo lesions [19]. Treatment responses of vitiligo
lesions could be different due to the disease duration and sex of
the patients. Therefore, we suggest that it is necessary to plan
the further studies with properly matched-patients on disease
duration and sex ratio.
In conclusion, nbUVB and topical Vitix® combination
treatment was not more effective than single nbUVB treatment in our
study. Although nbUVB treatment has a place, with the new
etiopathogenetic insights into vitiligo more effective therapies
can be developed. We can not rule out the possibility of a better
response to treatment if we had used a longer period. Therefore,
further studies with more patients and longer treatment periods are
necessary regarding the efficacy of nbUVB and topical
Vitix® combination treatment.
Acknowledgements
Financial support: Vitix® gels were supplied by Assos
pharmaceuticalse. Conflict of interest: none.
References
1 Ortonne JP. Vitiligo and other disorders of
hypopigmentation. In: Bolognia JL, Jorizzo JL,
Rapini RP, eds. Dermatology. Toronto: Elsevier, 2003: 947-73.
2 Koca R, Armutcu F, Altinyazar HC, Gürel A.
Oxidant-antioxidant enzymes and lipid peroxidation in generalized
vitiligo. Clin Exp Dermatol 2004; 29: 406-9.
3 Rokos H, Beazley WD, Schallreuter KU. Oxidative
stres in vitiligo: Photo-oxidation of Pterins produces
H2O2 and pterin–6-carboxylic acid. Biochem
Biophys Res Comm 2002; 292: 805-11.
4 Picardo M, Passi S, Morrone A,
Grandinetti M, Di Carlo A, Ippolito F. Antioxidant
status in the blood of patients with active vitiligo. Pigment Cell
Res 1994; 7: 110-5.
5 Nicolaidou E, Antoniou C, Stratigos AJ,
Stefanaki C, Katsambas AD. Efficacy, predictors of
response, and long-term follow-up in patients with vitiligo treated
with narrowband UVB phototherapy. J Am Acad Dermatol 2007; 56:
274-8.
6 Goktas EO, Aydin F, Senturk N, Canturk MT,
Turanli AY. Combination of narrow band UVB and topical
calcipotriol for the treatment of vitiligo. J Eur Acad Dermatol
Venereol 2006; 20: 553-7.
7 Aydin F, Senturk N, Sahin B, Bek Y,
Yuksel EP, Turanli AY. A practical method for the
estimation of vitiligo surface area: a comparison between the point
counting and digital planimetry techniques. Eur J Dermatol 2007;
17: 30-2.
8 Yildirim M, Baysal V, Inaloz HS, Can M.
The role of oxidants and antioxidants in generalized vitiligo at
tissue level. J Eur Acad Dermatol Venereol 2004; 18: 683-6.
9 Schallreuter KU, Wood JM, Berger J. Low
catalase levels in the epidermis of patients with vitiligo. J
Invest Dermatol 1991; 97: 1081-5.
10 Medrano EE, Nordlund JJ. Successful culture of
adult human melanocytes obtained from normal and vitiligo donors. J
Invest Dermatol 1990; 95: 441-5.
11 Schallreuter KU, Moore J, Wood JM,
Beazley WD, Gaze DC, Tobin DJ, et al. In vivo
and in vitro evidence for hydrogen peroxide
(H2O2) accumulation in the epidermis of
patients with vitiligo and its successful removal by a
UVB-activated pseudocatalase. J Investig Dermatol Symp Proc 1999;
4: 91-6.
12 Schallreuter KU. Successful treatment of oxidative
stress in vitiligo. Skin Pharmacol Appl Skin Physiol 1999; 12:
132-8.
13 Schallreuter KU, Moore J, Behrens-Williams S,
Panske A, Harari M. Rapid initiation of repigmentation in
vitiligo with Dead Sea climatotherapy in combination with
pseudocatalase (PC-KUS). Int J Dermatol 2002; 41: 482-7.
14 Schallreuter KU, Wood JM, Lemke KR,
Levenig C. Treatment of vitiligo with a topical application
pseudocatalase and calcium in combination with short term UVB
exposure: A case study on 33 patients. Dermatology 1995; 190:
223-9.
15 Patel DC, Evans AV, Hawk JL. Topical
pseudocatalase mousse and narrowband UVB phototherapy is not
effective for vitiligo: an open, single-centre study. Clin Exp
Dermatol 2002; 27: 641-4.
16 Schallreuter KU. Effectiveness of pseudocatalase
formulation in vitiligo. Clin Exp Dermatol 2003; 28: 562-3.
17 Schallreuter KU, Rokos H. Vitix®-a new treatment
for vitiligo? Int J Dermatol 2005; 44: 969-70.
18 Kostovic K, Pastar Z, Pasic A, Ceovic R.
Treatment of vitiligo with narrow-band UVB and topical gel
containing catalase and superoxide dismutase. Acta Dermatovenerol
Croat 2007; 15: 10-4.
19 De Francesco V, Stinco G, Laspina S,
Parlangeli ME, Mariuzzi L, Patrone P.
Immunohistochemical study before and after narrow band (311 nm) UVB
treatment in vitiligo. Eur J Dermatol 2008; 18: 292-6.
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